Introducing the Tripod Statement for Reporting Clinical Prediction Models


Gary Collins (@GSCollins) of the TRIPOD Steering Group introduces the TRIPOD Statement, which provides guidance for reporting clinical prediction models.

Clinical predictions are routinely made throughout medicine and at all stages in pathways of health care and are the basis for communicating risk or prognosis to patients and therefore inform the clinical decision making process. In the diagnostic setting, predictions are (for example) made as to whether a particular disease is present informing the referral for further testing, initiate treatment or reassure patients that a serious cause for their symptoms is unlikely. In the prognostic setting, predictions can be used for planning lifestyle or therapeutic decisions based on the risk of developing a particular outcome over a time period.

The multifactorial nature of making a clinical prediction makes it difficult for doctors to simultaneously combine and weight multiple risk factors to produce a reliable and accurate estimate of risk. Furthermore, it is unsurprising that numerous studies have shown that doctors are generally poor prognosticators, as they see relatively few cases and are given to cognitive biases.

Increasingly doctors, often based on recommendations in national clinical guidelines, are using multivariable prediction models to support and guide the clinical decision making process.  A clinical prediction model is a mathematical equation that relates multiple predictors for an individual to the probability (or risk) that a particular disease or condition is present or will occur in the future. Well known prediction models include the Framingham Risk score, Apgar Score, Ottawa Ankle Rules, EuroSCORE, Gail Model and the Simplified Acute Physiology Score (SAPS).

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Category: General | 1 Comment

FDA Voucher for Leishmaniasis Treatment: Can Both Patients and Companies Win?

Bernard Pécoul and Manica Balasegaram discuss whether drug companies have taken advantage of flaws in the FDA Priority Review Voucher program.

It sounded like a pure global health success story.

A company develops a drug for one of the most neglected diseases. As a reward, the company receives a voucher from the U.S. Food and Drug Administration (FDA). The company then sells this voucher, allowing the buyer to “fast-track” FDA approval for another product. A “win-win” in its truest sense: Innovation is rewarded while patients suffering from a deadly illness are given access to the fruits of scientific innovation.

Girl in a leishmaniasis clinic in Muzzaffarpur, India.  Image credit: Anita KHEMKA/DNDi

Leishmaniasis clinic in Muzzaffarpur, India. Image credit: Anita KHEMKA/DNDi

There are problems with this story, though.

What if the company did not actually develop the drug in question? What if patient access to the drug is far from secure?

When it was created in 2007, the FDA Priority Review Voucher (PRV) program came with hopes that it could incentivize research and development (R&D) for neglected diseases. Under the initial legislation, a developer that receives FDA approval for a drug to treat one of 16 diseases is eligible for a PRV, which allows the bearer to speed up approval for a drug application of their choice, or sell the voucher for another company to use. This reduces approval time from ten months on average to six – a crucial window for companies to get drugs on the market earlier than their competitors.

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Category: General | 1 Comment

One Million Deaths by Parasites

The end of 2014 saw the release of the Global Burden of Disease Study 2013 (GBD 2013), in which 240 causes of death were studied through a systematic analysis.  Among the important findings were that globally, parasitic diseases caused more than one million deaths in the year 2013.

To no one’s surprise, malaria was by far the major parasitic disease killer in 2013, causing over 850,000 deaths, with many of those deaths in African children under the age of five infected with Plasmodium falciparum.  However, kinetoplastid infections – leishmaniasis, Chagas disease, and African trypanosomiasis – caused the deaths of over 80,000 people, while two intestinal protozoan infections – cryptosporidiosis and amoebiasis – resulted in over 50,000 deaths.

A breakdown of those deaths is shown in Table 1.

Table 1.  Deaths caused by parasitic diseases in 2013

Parasitic Disease Global Deaths in 2013
Malaria 854,600
Leishmaniasis (Kala-azar) 62,500
Cryptosporidiosis 41,900
Amoebiasis 11,300
Chagas disease 10,600
African Trypanosomiasis   6,900
Schistosomiasis   5,500
Ascariasis   4,500
Cystic Echinococcosis   2,200
Cysticercosis      700
Total Deaths from Parasitic Infections 1,000,700

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Category: General | 3 Comments

Is Margaret Chan Really to Blame for the Delayed Ebola Response?

Sara Gorman (@saragorm) discusses recent criticism of WHO Director-General Margaret Chan and whether the focus should be on failures in preparation rather than response.

A January 6 article in the New York Times suggested that WHO Director-General Margaret Chan’s response to the Ebola crisis was woefully inadequate. The article notes that it took 1,000 Ebola deaths in Africa and the spread of the disease to Nigeria for the Chan to proclaim a global emergency. Citing criticisms of Chan’s response to the SARS epidemic as a public health administrator in Hong Kong, the article accuses the current WHO head of conceding too heavily to local governments. The article claims that she relied too heavily on African regional offices to manage the response when her agency should have stepped in more aggressively earlier. But the history of public responses to infectious disease announcements, as well as tragically underfunded global disease surveillance systems, suggest that, while Chan may not have done everything she could, the story is much more complex than it seems.

Image credit: star5112, Flickr

Image credit: star5112, Flickr

Sounding the alarm bell on an infectious disease threat and taking extreme measures such as quarantine and travel bans is not without risk. American history is littered with examples of harmful infectious disease panic. More often than not, American responses to infectious disease threats tend to tap into embedded racial tensions. We only need to look at vicious attacks on African boys at a Bronx, NY school in October, to the sounds of the nickname “Ebola,” to understand that these dynamics are still very much at play. Chan herself certainly knows the harms of acting perhaps too quickly in response to what seems like a global infectious disease crisis. In 2009, Chan was harshly criticized for supposedly “overreacting” to the H1N1 threat.

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Category: Ebola, Policy, Public, WHO | 1 Comment

TDR Reflects on 40 Years

Nigeria CDI Projects July 07 305

Image Credit: WHO/TDR/Andy Craggs
A multi-country study in Africa investigating the efficacy of community health workers to deliver multiple interventions for malaria, onchocerciasis, tuberculosis and infant vitamin A distribution.

In April of 1974, the 27th session of the World Health Assembly called for the “intensification of activities in tropical disease research” and the “strengthening of research and training activities”, particularly in developing countries. By November of that year, TDR, the Special Programme for Research and Training in Tropical Diseases, was in operation. The main principles were to promote and conduct research equitably, and to provide access to this knowledge and the resulting tools to the most vulnerable and hard to reach people.

It has been 40 years since that initial start, and many lessons have since been learned. In this special collection of 7 articles, former and current TDR staff provide their views on key challenges and lessons learned during the 40 year history, and explain how and why the approaches and workplans changed through time. This includes the type of research supported, the way it was conducted and even the diseases covered. As the needs in the countries evolved, so too has the Programme.

New TDR Collection Historical Profiles and Perspectives Articles:

Shaping the Research Agenda

From Bright Ideas to Tools: The Case of Malaria

Applied Research for Better Disease Prevention and Control

What Have We Learned from 40 Years of Supporting Research and Capacity Building?

Vector Research Addressing Country Control Needs

A Changing Model for Developing Health Products for Poverty-Related Infectious Diseases

Strengthening research capacity – TDR’s evolving experience in Low- and Middle- Income Countries

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Category: General | 1 Comment

Supporting Those Who Go to Fight Ebola

Michelle Mello, Maria Merritt, and Scott Halpern discuss healthcare institutions’ responsibilities to support their employees’ volunteer efforts in Ebola-affected regions. This is a pre-publication version of a manuscript that has been accepted by PLOS Medicine as a Guest Editorial.

Image credit: DFID, Flickr

Image credit: DFID, Flickr

The Ebola epidemic is testing virtually every aspect of the public health and healthcare systems in the U.S., including healthcare institutions’ public service commitments. Although the number of cases in the U.S. remains very small, an extraordinary amount of public and hospital resources have been devoted to preparing for new cases domestically [1, 2, 3, 4] In contrast, although US hospital and medical professional organizations have called for an “enhanced focus” on containing Ebola in West Africa [5], there is a striking absence of public commitments on the part of US healthcare institutions to contribute to the containment effort.

By quickly mobilizing qualified health care professionals (HCPs) to work in Guinea, Liberia, and Sierra Leone, U.S. hospitals could not only meet the needs of desperate patients, but could contain Ebola at its source, averting global risk [6]. Yet, US institutions’ response to the West African epidemic has been muted thus far. Reports indicate that many institutions—even those with a tradition of sending personnel to respond to other humanitarian crises—have asked their HCPs to stay home this time [7, 8, 9].

Although some academic medical centers (AMCs) in the U.S. have invoked their usual policy that the university will support overseas work with services such as emergency travel assistance, others have specified that staff who serve in Ebola-affected regions do so in their personal capacity, not as employees. Still others have strongly cautioned against serving, prohibited official travel to affected regions, required staff to take vacation time or unpaid leave for 21 days following repatriation before returning to work, and made clear that the university will not assist if the HCP falls ill.

The concerns that may motivate hospitals to discourage volunteers do not outweigh the countervailing considerations. At a minimum, institutions ought not to impede service; ideally, they would promote it.

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Category: Ebola, Global Health, Open Access | 5 Comments

How Knowledge Sharing Moves Countries Towards UHC

Stefan Nachuk, Amanda Folsom, and Nathaniel Otoo are members of the Joint Learning Network for Universal Health Coverage (JLN). The JLN provides a forum for countries to learn from one another and work together towards achieving UHC.

JLN LogoAs the global movement towards UHC -as a post-2015 goal- continues to gain momentum, low and middle-income countries will need to overcome a number of design and technical challenges within their health systems to achieve UHC. Health systems strengthening and reform are very challenging– both in terms of designing policies and programs and effectively implementing them to assure the desired impact. There is often a knowledge gap between “how to” implement health systems changes and traditional research methods and technical assistance. Much knowledge about how to effectively design and implement systems change resides in practitioners who have led or are in the process of leading systems, programs, and reform processes.

Almost 5 years ago, practitioners in countries such as Ghana, India, and Thailand who were working to achieve universal health coverage (UHC) in their countries had no way to connect with each other. These practitioners tried to find answers to their implementation challenges within the myriad of articles and reports about universal coverage. They typically found that traditional technical assistance approaches tended to focus on what to implement, not how. There was a paucity of forums specifically designed for them to learn from one another and co-develop new knowledge and solutions about how to achieve UHC.

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Category: General | 2 Comments

Ebola Virus Disease: Platform for North-South Collaboration Urgently Needed

Solomon Nwaka and colleagues summarize the outcomes of the September meeting of the Board, and Scientific and Advisory Committee (STAC) of the African Network for Drugs and Diagnostics Innovation (ANDI) on Ebola, and outline the next steps for combating EVD.

Image credit: NIAID, Flickr

Image credit: NIAID, Flickr

The World Health Organization (WHO) has characterized the current Ebola Virus Disease (EVD) crisis as not just a public health crisis, but also a social, humanitarian and economic crisis, and a threat well beyond the outbreak zones. Indeed, the disease has been reported in Spain and USA. The UN General Assembly has established the United Nations Missions for Ebola Emergency Response (UNMEER), to join governments and international partners to respond to the Ebola outbreak. A number of developed and emerging countries, World Bank, African Development Bank, Philanthropic Foundations, and Non-Governmental Organizations including Doctors Without Borders, have made financial and logistical contributions to control the spread and reduce suffering. These resources have been deployed to provide surveillance and contact tracing, mobile testing facilities, isolation and treatment facilities, medical staff, as well as to help the expedited development of potential therapeutic agents. Despite these efforts, the EVD outbreak in West Africa continues, with over 17,256 cases and 6,113 deaths as of December 4, 2014; and estimates of up to 1.4 million cases of Ebola infection by January 2015.

Within Africa, countries such as Nigeria, The Gambia, and Botswana have made monetary contributions in support of the crisis, while others like Malawi, South Africa and Democratic Republic of Congo have provided medical supplies. The Economic Community of West African States (ECOWAS) is implementing a strategy for accelerated response while the African Union has approved a humanitarian mission called the AU Response to Ebola Outbreak in West Africa (ASEOWA). The long awaited establishment of an African Centre for Disease Control and Prevention (ACDCP) now appears to have been fast tracked by the AU, to help in addressing emergencies in a timely and effective manner. An African Public Health Emergency Fund (APHEF) provided initial support to affected countries, but was inadequate to cope with the rage of the epidemic due to poor subscription by countries.

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Category: Ebola, Global Health, Policy, Public | 2 Comments

Neglected Tropical Diseases that Kill

According to the latest (November 28) figures from the World Health Organization (WHO) and US Centers for Disease Control and Prevention, almost 6,000 people have died so far in the 2014 Ebola outbreak in West Africa, with estimates that the deaths will easily exceed 7,000 deaths before year’s end.

There is no question that Ebola virus infection is one of the most lethal of all of the neglected tropical disease (NTD) pathogens, but on a global scale there are a number of other NTDs that also cause large numbers of deaths.

The WHO currently lists 17 major disease conditions as NTDs.  Shown in Fig. 1 is an illustration from our previous publication in PLOS Neglected Tropical Diseases that compares the proportion of disability-adjusted life years (DALYs) that result either from disability (YLDs – years lived with a disability) colored in blue, or death (YLLs – years of life lost) colored in orange.   It’s clear that there is a lot more blue than orange meaning that most of the world’s NTDs are disablers rather than killers.  But there are also important exceptions such as the kinetoplastid infections, including leishmaniasis (kala-azar), African sleeping sickness, and Chagas disease, as well as the viral infections rabies and dengue fever which also represent major killers.  Schistosomiasis, which is a major disabler, is another important cause of mortality in Africa.

Hotez et al.

Hotez et al.

Indeed, if we compare the number of people who have died in this year’s Ebola epidemic with the number of deaths caused by NTDs from the Global Burden of Disease Study 2010, we find that there are some very serious and lethal NTDs that get very little attention.  At least six NTDs kill more people each year than all those who perished from Ebola virus infection this year.

Our takeaway is that while we urgently need new drugs, diagnostics, and vaccines for Ebola virus infection, the same could be said for all of the NTDs listed in Table 1.  As the global policy leaders in the United States, Europe, and elsewhere meet in the coming weeks and months, we hope they will consider new Ebola virus technologies in the context of each of our planet’s killer NTDs.

Table 1. Deaths from the NTDs and Ebola virus infection (modified from Refs. 1 and 3)

Neglected Tropical Disease Deaths Year
Leishmaniasis 51,600 2010
Rabies 26,400 2010
Dengue fever 14,700 2010
Schistosomiasis 11,700 2010
Chagas disease 10,300 2010
African trypanosomiasis   9,100 2010
Ebola virus infection 6,000-7,000 2014
Intestinal nematode infections   2,700 2014
Cysticercosis   1,200 2014
Echinococcosis   1,200 2014
Category: General | 5 Comments

Ebola: MSF Should Not Replace Governmental Responsibilities

A version of this was published in Le Temps on 31 October 2014

Thomas Nierle and Bruno Jochum of Médecins Sans Frontières emphasize the responsibility of governments to lead the response to disasters like the Ebola outbreak.

Image credit: Francois Dumont/MSF

Image credit: Francois Dumont/MSF

MEP Charles Goerens, rapporteur on Ebola to the European Parliament’s Committee on Development, recently declared (audio report in French) in a European Council meeting that this epidemic is “the first major international crisis in which the lead should be given to an NGO – in this case, Médecins Sans Frontières”.

Given that we have repeatedly called for greater leadership from the international community, including the European Union, this proposal took us by surprise. We have interpreted this appeal, coming from an MEP who has also publicly criticised the inadequate reactions of European states in the face of the epidemic, as a symptom of the failure of existing public response mechanisms and even more so, of the huge collective difficulty in taking action.

When a disaster occurs – whether an epidemic, a natural disaster or any other event with similar effects – the primary responsibility for helping the victims as quickly as possible and minimising the impact on society falls on the affected states. Because public authorities are in the front line for initiating and managing the emergency response, the legitimacy to act can only lie with governments and their collective institutions, as embodied by the United Nations. Not addressing a critical health crisis and therefore abstaining from coordinating healthcare for entire populations would represent utter failure on behalf of States and international institutions whose mandate it is. Such a vacuum would be as worrying as it would be politically unacceptable.

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Category: Ebola, Global Health, MSF | Tagged | 2 Comments